Crystallization from solution of pharmaceutically active compounds or their intermediates is the typical method of purification used in industry. The integrity of the crystal structure, or crystal habit, that is produced and the particle size of the end product are important considerations in the crystallization process.
High bioavailability and short dissolution time are desirable or often necessary attributes of the pharmaceutical end product. However, the direct crystallization of small sized, high surface area particles is usually accomplished in a high supersaturation environment which often results in material of low purity, high friability, and decreased stability due to poor crystal structure formation. Because the bonding forces in organic crystal lattices generate a much higher frequency of amorphism than those found in highly ionic inorganic solids, "oiling out" of supersaturated material is not uncommon, and such oils often solidify without structure.
Slow crystallization is a common technique used to increase product purity and produce a more stable crystal structure, but it is a process that decreases crystallizer productivity and produces large, low surface area particles that require subsequent high intensity milling. Currently, pharmaceutical compounds almost always require a post-crystallization milling step to increase particle surface area and thereby improve their bioavailability. However, high energy milling has drawbacks. Milling may result in yield loss, noise and dusting, as well as unwanted personnel exposure to highly potent pharmaceutical compounds. Also, stresses generated on crystal surfaces during milling can adversely affect labile compounds. Overall, the three most desirable end-product goals of high surface area, high chemical purity, and high stability cannot be optimized simultaneously using current crystallization technology without high energy milling.
One standard crystallization procedure involves contacting a supersaturated solution of the compound to be crystallized with an appropriate "anti-solvent" in a stirred vessel. Within the stirred vessel, the anti-solvent initiates primary nucleation which leads to crystal formation, sometimes with the help of seeding, and crystal digestion during an aging step. Mixing within the vessel can be achieved with a variety of agitators (e.g., Rushton or Pitched blade turbines, Intermig, etc.), and the process is done in a batchwise fashion.
When using current reverse addition technology for direct small particle crystallization, a concentration gradient can not be avoided during initial crystal formation because the introduction of feed solution to anti-solvent in the stirred vessel does not afford a thorough mixing of the two fluids prior to crystal formation. The existence of concentration gradients, and therefore a heterogeneous fluid environment at the point of initial crystal formation, impedes optimum crystal structure formation and increases impurity entrainment. If a slow crystallization technique is employed, more thorough mixing of the fluids can be attained prior to crystal formation which will improve crystal structure and purity, but the crystals produced will be large and milling will be necessary to meet bioavailability requirements.
Another standard crystallization procedure employs temperature variation of a solution of the material to be crystallized in order to bring the solution to its supersaturation point, but this is a slow process that produces large crystals. Also, despite the elimination of a solvent gradient with this procedure, the resulting crystal characteristics of size, purity and stability are difficult to control and are inconsistent from batch to batch.
The novel process of this invention utilizes impinging jets to achieve high intensity micromixing in the crystallization process. High intensity micromixing is a well known technique where mixing-dependent reactions are involved. Feeding strategies as they relate to precipitation were addressed by Mersmann, A. and Kind, M., Chemical Engineering Aspects of Precipitation from Solution, Chem. Eng. Technol., V. 11, p. 264 (1988). Notable among other papers recently addressing the effect of micromixing in reaction processes are Garside, J. and Tavare, N. S., Mixing, Reaction and Precipitation: Limits of Micromixing in an MSMPR Crystallizer, Chem. Eng. Sci., V. 40, p. 1485 (1985); Pohorecki, R. and Baldyga, J., The Use of a New Model of Micromixing for Determination of Crystal Size in Precipitation, Chem. Eng. Sci., V. 38, p. 79 (1983). However, the use of high intensity micromixing is not the norm in current crystallization technology where no chemical reaction is involved.
Impinging jets are used for micromixing routinely in reaction injection moulding (RIM) technology in the plastics industry but not for the purpose of causing crystallization. The use of an impinging jet device in a crystallization process to achieve intense micromixing is novel. Whether feed material is relatively pure or impure, the use of impinging jets results in crystal characteristics superior to those that result from standard crystallization methods.
Now with the present invention there is provided a method for crystallization of pharmaceutical compounds or their intermediates which directly produces high surface area end product crystals with greatly improved stability and purity and thereby eliminates the need for subsequent high intensity milling to meet bioavailability requirements. By removing the need for milling, the novel jet process avoids associated problems of noise and dusting, cuts yield loss, and saves the time and extra expense incurred during milling. It also removes an extra opportunity for personnel contact with a highly potent pharmaceutical agent, or for adverse effects on labile compounds. The small particle size attained with the jet process is consistent within a single run and as shown in Table 1, results are reproducible between runs. Reproducibility is an attribute of this process that is not common to "reverse addition" methods typically used to produce small crystals.
The pure, high surface area particles that result from the jet process also display superior crystal structure when compared to particles formed via standard slow crystallization plus milling methods using the same quality and kind of feed compound. Improvements in crystal structure result in decreases in decomposition rate and therefore longer shelf-life for the crystallized product or a pharmaceutical composition containing the crystallized material. As shown in Table 2, the material produced by the jet process exhibits more consistent accelerated stability results than that produced by the conventional batch process.
The purity of crystallized material produced from the jet process is superior to that from standard reverse addition direct small particle crystallization, as demonstrated with simvastatin using high performance liquid chromatography (HPLC) in Table 3. Standard slow batch crystallization affords product purity comparable to that afforded by the jet process, but the jet process is superior because, as noted above, in addition to high purity, it also provides higher quality crystal habit and increased particle surface area thereby eliminating the need for milling.
Jet process crystallization is suited for continuous processing. Standard crystallization methods are generally run in a batchwise fashion. Continuous processing affords two advantages. First, the same amount of feed compound can be crystallized in significantly less volume via continuous processing than would be possible using a batch by batch method. Second, continuous processing enhances reproducibility of results because all the material crystallizes under uniform conditions. Such uniformity is not possible using batch methods in which concentration, solubility and other parameters change with time.
TABLE 1 ______________________________________ JET CRYSTALLIZED SIMVASTATIN Surface Area Batch (m.sup.2 /g) at 45-55.degree. C. ______________________________________ 1 3.37* 2 2.57* 3 2.88* 4 3.56* 5 3.35 6 2.55 Mean: 3.05 Standard Deviation: 0.40 ______________________________________ *Run at 50-51.degree. C.
TABLE 2 ______________________________________ 60.degree. C. ACCELERATED STABILITY TEST Surface Weeks (at 60.degree. C.) Temp. Batch Area 0 1 2 4 6 8 .degree.C. ______________________________________ JET CRYSTALLIZED SIMVASTATIN 1 2.4 98.7 99.4 96.8 95.1 97.2 68 2 4.0 98.9 92.5 93.3 98.1 95.1 55 3 5.5 99.3 96.5 88.5 93.4 85.7 55 4 4.6 98.8 95.1 96.4 86.0 80.1 55 SLOW BATCH CRYSTALLIZED SIMVASTATIN (MILLED) 1 3.0 98.9 95.5 95.7 95.0 95.0 * 2 3.3 99.1 94.9 94.3 83.6 95.0 * 3 2.6 99.0 98.2 95.9 93.0 93.5 * 4 2.7 99.2 98.4 95.3 95.4 82.8 * 5 99.7 98.3 98.0 81.3 36.6 * 6 99.2 94.0 89.0 77.8 34.0 * ______________________________________ *Heat-cool process used.
TABLE 3 ______________________________________ Simvastatin HPLC 969 Crystallization Temp. Purity Impurity** Method* (.degree.C.) (Weight %) (Weight %) ______________________________________ Continuous 50 99.0 &lt;0.1 Impinging Jets Continous 25 98.6-99.0 0.2-0.4 Impinging Jets Batch Reverse 25 98.7 0.7 Addition Slow Batch Process 99.0 &lt;0.1 Product Specification &gt;98.5 &lt;0.5 ______________________________________ *50:50 Volumetric ratio of MeOH:H.sub.2 O used with impinging jet method; final volumetric ratio of 50:50 MeOH:H.sub.2 O used with reverse addition and slow batch methods. **Open ring form of simvastatin.